Re-Purposing Sapropterin (Kuvan) for ACTA2-Related Multisystemic Smooth Muscle Dysfunction Syndrome: A Translational...

Area of Science:

• Genetics and Molecular Biology
• Cardiovascular Research
• Pharmacology

Background:

• Multisystemic smooth muscle dysfunction syndrome (MSMDS) is an ultra-rare genetic disorder.
• It is linked to ACTA2 gene mutations, causing severe cerebrovascular disease, aortic aneurysms, and smooth muscle dysfunction.
• Current treatment options for MSMDS are limited.

Purpose of the Study:

• To identify potential therapeutic agents for ACTA2-related MSMDS.
• To investigate the efficacy of sapropterin dihydrochloride (Kuvan) in restoring actin polymerization disrupted by the p.R179H mutation.
• To evaluate the clinical effect of Kuvan in a pediatric patient with ACTA2-MSMDS.

Main Methods:

• In silico drug screening and molecular dynamics simulations were employed to identify candidate drugs.
• Patient-derived fibroblasts were used to assess the impact of Kuvan on actin organization.
• An off-label, single-patient (n-of-1) clinical trial was conducted to evaluate treatment outcomes.

Main Results:

• Sapropterin dihydrochloride (Kuvan) was identified as a potential therapeutic candidate capable of restoring actin polymerization.
• Kuvan treatment improved actin organization in patient-derived fibroblasts.
• The pediatric patient showed cerebrovascular stabilization and clinical improvement during longitudinal follow-up.

Conclusions:

• Sapropterin dihydrochloride (Kuvan) demonstrates potential as a disease-modifying therapy for ACTA2-related vasculopathies.
• This study provides initial human evidence for Kuvan's therapeutic effect in MSMDS.
• Further research is warranted to confirm efficacy and elucidate underlying mechanisms.